Over 90% of the cells in the human body are microbes, the majority of which reside in bacterial communities (microbiota) that inhabit the large intestine. Recent advances in high-throughput microbiota sequencing (metagenomics) provide a powerful tool for profiling the previously hidden microbial diversity in the gut. For example, metagenomic analysis shows that the large intestine is host to a diverse bacterial community whose structure, at the phylum level, is maintained through unknown mechanisms. The bacterial species dominating the microbiota in the large bowel are strict anaerobes, which lack the ability to respire oxygen and rely on fermentation of complex polysaccharides for growth (Mahowald et al., Proc. Natl. Acad. Sci. U.S.A., 106:5859-5864 (2009)). Towering above all other are obligate anaerobic bacteria belonging to the phyla Bacteroidetes (class Bacteroidia) and Firmicutes (class Clostridia) (Eckburg et al., Science, 308:1635-1638 (2005)). The dominance of obligate anaerobic bacteria belonging to the classes Bacteroidia and Clostridia is a conserved feature of bacterial communities inhabiting the large intestine of both humans and mice (Eckburg et al., Science, 308:1635-1638 (2005); Ley et al., Proc. Natl. Acad. Sci. U.S.A., 102:11070-11075 (2005)).
However, conditions of gastrointestinal inflammation can lead to a microbial imbalance (dysbiosis) characterized by phylum-level changes in the microbiota composition, including a marked decrease in the representation of obligate anaerobic bacteria and an increased relative abundance of facultative anaerobic bacteria. For example, acute intestinal inflammation triggered by pathogenic Enterobacteriaceae (class Gammaproteobacteria, phylum Proteobacteria), such as Salmonella enterica or Citrobacter rodentium, is accompanied by changes in the bacterial community structure that are marked by an outgrowth of the respective facultative anaerobic pathogen (Barman et al., Infect. Immun., 76:907-915 (2008); Lupp et al, Cell Host Microbe, 2:119-129 (2007); Stecher et al., PLoS Biol., 5:2177-2189 (2007)). Similarly, a reduced relative abundance of strictly anaerobic members of the classes Bacteroidia and Clostridia, and a concomitant increased relative abundance of facultative anaerobic commensal bacteria belonging to the family Enterobacteriaceae or to the class Bacilli (phylum Firmicutes) is seen in individuals with inflammatory bowel disease (IBD) (Baumgart et al., ISME J., 1:403-418 (2007); Frank et al., Proc. Natl. Acad. Sci U.S.A., 104:13780-13785 (2007); Giaffer et al., J. Med. Microbiol., 35:238-243 (1991); Gophna et al., J. Clin. Microbiol., 44:4136-4141 (2006); Krook et al., J. Clinical Pathology, 34:645-650 (1981); Seksik et al., Gut, 52:237-242 (2003); Walker et al., ISME J., 5:220-230 (2011)).
A marked decrease in the representation of obligate anaerobic Bacteroidia and Clostridia and an increased relative abundance of facultative anaerobic Enterobacteriaceae can also be observed in mice when colitis is induced chemically (Lupp et al., Cell Host Microbe, 2:119-129 (2007)) or through genetically engineered immune defects (Garrett et al., Cell Host Microbe, 8:292-300 (2010)). The dense bacterial communities inhabiting the distal gut compete fiercely for a limited quantity of diet-derived or host mucus-derived carbohydrate available for fermentation (reviewed in, e.g., Fischbach and Sonnenburg, Cell Host Microbe, 10:336-347 (2011); Koropatkin et al., Nat. Rev. Microbiology, 10:323-335 (2012)). Changes in the diet can alter the microbial community structure on the species level; however, the dominance of obligate anaerobic Clostridia and Bacteroidia over the facultative anaerobic Enterobacteriaceae remains untouched (Faith et al., Science, 333:101-104 (2011); Martinez et al., PLoS One, 5:e15046; Sonnenburg et al., Cell, 141:1241-1252 (2010); Walker et al., ISME J., 5:220-230 (2011); Wu et al., Science, 334:105-108 (2011)).
Thus, a need exists for therapeutic agents and methods for inhibiting anaerobic respiration by gut microbes, thereby reducing gastrointestinal inflammation. The present invention satisfies this need and provides related advantages as well.